Press Release: Boehringer Presents Phase 3 Results for Dabigatran Etexilate

Phase 3 Results for Dabigatran Etexilate, an Investigational Oral Anticoagulant, Presented Today at the XXIst Congress of the International Society on Thrombosis and Haemostasis RIDGEFIELD, Conn., July 11 -- Phase 3 results from the RE-NOVATE(TM) trial demonstrated that oral dabigatran etexilate once daily, administered for an average of 33 days, was non-inferior to enoxaparin, also administered for an average of 33 days, in preventing venous thromboembolism (VTE) and all-cause mortality after total hip replacement surgery. In this trial, the rate of major bleeding associated with dabigatran etexilate was similar to enoxaparin. The incidence of liver enzyme elevations and acute coronary events during the treatment or during the follow-up period did not differ significantly between the treatment groups. These data were presented at the XXIst Congress of the International Society on Thrombosis and Haemostasis (ISTH) today.(i) In clinical trials, dabigatran etexilate is given orally once daily and does not require titration or coagulation monitoring. Results of the RE-NOVATE trial showed that both oral doses (220mg; 150 mg) of dabigatran etexilate were non-inferior to injected enoxaparin at reducing the risk of thromboembolic disease after primary elective total hip replacement surgery when given for the extended average time period of 33 days. The incidences for the primary efficacy composite endpoint of total VTE and all-cause mortality were 6.0% (dabigatran 220 mg), 8.6% (dabigatran 150 mg), and 6.7% (enoxaparin 40 mg). The incidences of total VTE and all-cause mortality in both dabigatran dose groups were within the pre-specified non- inferiority margin of 7.7%. Safety was evaluated for 3,463 patients receiving study treatment. The incidences of major bleeding events were similar in all treatment groups, 2.0% (dabigatran 220 mg), 1.3% (dabigatran 150 mg), and 1.6% (enoxaparin 40 mg). Also presented at ISTH was a pooled analysis of major VTE and VTE-related mortality after primary elective knee and hip replacement surgery across more than 8,000 randomized patients that were included in the phase 3 primary VTE prevention program (RE-MODEL(TM), RE-MOBILIZE(TM) and RE-NOVATE studies).(ii) The pooled analysis concluded that dabigatran etexilate was non-inferior to enoxaparin in the prevention of major VTE and VTE-related mortality after both knee and hip replacement. Major VTE rates for both doses of dabigatran etexilate were similar to enoxaparin -- major VTE and VTE-related mortality occurred in 3.8% of the 150 mg dabigatran etexilate group and 3.0% of the 220 mg dabigatran etexilate group, versus 3.3% of the enoxaparin group. Major bleeding events were similar across all treatment groups (1.1%, 1.4% and 1.4% respectively). As part of the safety evaluation, patients were monitored frequently for liver enzyme elevations. Those patients with elevations of >3 x ULN (upper limit of normal) were infrequent and similar across all treatment groups. In addition, treatment emergent acute coronary syndrome (ACS) events were infrequent and similar across treatment groups. Results from the European knee replacement trial (RE-MODEL) were previously presented in December 2006 (iii) at the Annual Meeting of the American Society of Hematology. The RE-MODEL study was a multi-national, randomized, double-blind, non-inferiority trial involving 2,076 patients comparing dabigatran etexilate with enoxaparin in the prevention of VTE in patients undergoing primary elective total knee replacement surgery. Patients were randomized to either oral dabigatran 150 mg or 220 mg once daily or 40 mg enoxaparin administered by subcutaneous injection once daily. In the U.S., the approved dose of enoxaparin for this indication is 30 mg, administered twice daily by subcutaneous injection. Results from the North American knee replacement trial (RE-MOBILIZE) were also presented at ISTH.(iv) The RE-MOBILIZE study was a randomized, double- blind, non-inferiority trial involving 2,615 patients comparing 150 mg or 220 mg once-daily or 30 mg twice-daily enoxaparin administered by subcutaneous injection. The primary endpoint of a composite of total VTE, and all-cause mortality was not achieved (33.7% and 31.1% for 150 mg and 220 mg dabigatran etexilate respectively, versus 25.3% enoxaparin). The difference in these results was primarily due to the incidence of asymptomatic deep vein thrombosis (DVT) detected by protocol required venography at the end of therapy. Major VTE occurred at similar rates across all treatment groups (3.0% and 3.4% for 150 mg and 220 mg dabigatran etexilate respectively, versus 2.2% enoxaparin). Although major bleeding events were more common in the enoxaparin group (1.4%) compared to the dabigatran 220 mg group (0.6%) and the dabigatran 150 mg group (0.6%), these differences were not statistically significant. About dabigatran etexilate Dabigatran etexilate is an investigational oral direct thrombin inhibitor that specifically and reversibly inhibits thrombin, the key enzyme for blood clot formation, and is currently in phase 3 development. It is administered as a once daily oral dose that does not require titration or coagulation monitoring. Further studies investigating dabigatran etexilate Dabigatran etexilate is being investigated in multiple phase 3 trials that are designed to investigate the oral direct thrombin inhibitor as a potential treatment and prophylaxis for several thromboembolic disease conditions. The phase 3 clinical trial program is expected to involve more than 27,000 patients from Asia, Australia, Europe, the Americas, and South Africa. Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies. The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 137 affiliates in 47 countries and approximately 38,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine. In 2006, Boehringer Ingelheim posted net sales of US $13.3 billion (10.6 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development. For more information, please visit http://us.boehringer-ingelheim.com/. References i. Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate is effective and safe for the extended prevention of venous thromboembolism following total hip replacement. Abstract presented at XXIst Congress of the International Society on Thrombosis and Haemostasis in Geneva, Switzerland, July 2007 ii.Caprini JA, Hwang E, Hantel S et al. The oral direct thrombin inhibitor dabigatran etexilate is effective and safe for prevention of major venous thromboembolism following orthopaedic surgery. Abstract presented at XXIst Congress of the International Society on Thrombosis and Haemostasis in Geneva, Switzerland, July 2007 iii. Eriksson BI, Dahl OE, van Dijk CN, et al. A New Oral Anticoagulant, Dabigatran Etexilate, is Effective and Safe in Preventing Venous Thromboembolism after Total Knee Replacement Surgery (The RE-MODEL Trial). Blood (ASH Annual Meeting Abstracts) 2006;108: Abstract 573 iv. Friedman RJ, Caprini JA, Comp PC et al Dabigatran Etexilate Versus Enoxaparin In Preventing Venous Thromboembolism Following Total Knee Arthroplasty. Abstract presented at XXIst Congress of the International Society on Thrombosis and Haemostasis in Geneva, Switzerland, July 2007 Boehringer Ingelheim Pharmaceuticals, Inc.

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